Rational Drug Design Utilizing Halogen Atoms And Cyano Groups

"Functional group effect" in the field of medicinal chemistry is a phenomenon where substitution of a functional group on a lead compound leads to an improved binding affinity or drug-like properties.However,"functional group effect" has been mainly used retrospectively to summarize the experimental results,utilizing these functional groups in prospective fashion in drug discovery is desired.This thesis aimed at developing computational strategies to utilize the halogen atom and cyano group by revealing the contributions of binding-site waters in protein-ligand binding,and providing rational guidance for utilization of halogen atom and cyano group in structure-based drug design.We found that halogen atoms involved in halogen bond interactions could replace specific binding-site waters upon ligand binding;this replacement is accompanied by a potential gain in entropy from the release of ordered binding-site waters into the bulk solvents.Combining with the geometrical characteristics of halogen bonds,we proposed a computational strategy for utilizing halogen atoms.Based on the strategy,we explored halogen bonds between the scaffold of ibrutinib and its kinase target protein Bruton's tyrosine kinase,and halogen bonds between halogenated doxepin and 5-hydroxytryptamine receptor 2B.Both structure-activity relationship studies and binding free energy calculations validated these designed halogen bond interactions,thus strongly proved the feasibility of the strategy.Our works provided promising strategies and new perspectives for utilization of halogens in structure-based drug design.We surveyed the roles of cyano groups in protein-ligand interactions and summarized the interaction patterns and structural characteristics of cyanos in protein-ligand complex structures.We also found that cyanos involved in hydrogen bonds with backbone amide could replace specific binding-site waters upon ligand binding.In addition,our free energy perturbation calculations could reproduce the binding free energy differences induced by cyanos.Thus,we proposed a computational strategy for utilizing cyano groups by incorporating geometrical characteristics,water replacement and free energy perturbation calculation.Based on the strategy,cyano-substituted vandetanib was designed and assessed,the experimental results proved the feasibility of the strategy.Our works provided promising strategies and new perspectives for utilization of cyanos in structure-based drug design.